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Early pharmacological studies of Aconitum and Delphinium sp. alkaloids suggested that these neurotoxins act at site 2 of voltage-gated Na + channel and allosterically modulate its function. Understanding structural requirements for these compounds to exhibit binding activity at voltagegated Na+ channel has been important in various fields. This paper reports quantum-chemical studies and quantitative structure-activity relationships (QSARs) based on a total of 65 natural alkaloids from two plant species, which includes both blockers and openers of sodium ion channel. A series of 18 antagonist alkaloids (9 blockers and 9 openers) have been studied using AM1 and DFT computational methods in order to reveal their structure-activity (structure-toxicity) relationship at electronic level. An examination of frontier orbitals obtained for ground and protonated forms of the compounds revealed that HOMOs and LUMOs were mainly represented by nitrogen atom and benzyl/benzoylester orbitals with -OH and -OCOCH 3 contributions. The results obtained from this research have confirmed the experimental findings suggesting that neurotoxins acting at type 2 receptor site of voltage-dependent sodium channel are activators and blockers with common structural features and differ only in efficacy. The energetic tendency of HOMO-LUMO energy gap can probably distinguish activators and blockers that have been observed. Genetic Algorithm with Multiple Linear Regression Analysis (GA-MLRA) technique was also applied for the generation of two-descriptor QSAR models for the set of 65 blockers. Additionally to the computational studies, the HOMO-LUMO gap descriptor in each obtained QSAR model has confirmed the crucial role of charge transfer in receptor-ligand interactions. A Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author Manuscript number of other descriptors such as logP, I BEG , nNH2, nHDon, nCO have been selected as complementary ones to LUMO and their role in activity alteration has also been discussed. HHS Public Access

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747.945+547.79+548.737 G. Genzhemuratova, M. G. Levkovich, and Kh. M. ShakhidoyatovN-Acyl cytisine derivatives were synthesized by acylation with acetic anhydride; benzoyl and o-bromo-and p-nitrobenzoyl chlorides; and crotonyl and cinnamoyl chlorides. The structures of the synthesized compounds were studied using IR, PMR, and x-ray structure analysis (XSA). PMR spectra of the N-acylcytisines in solution typically had two rotational isomers around the N12-CO bond. Conformational analysis was performed using XSA for the position of the acyl group relative to the cytisine core. Bond lengths and angles of the acyl groups involved in the conjugation were analyzed.The broad spectrum of biological activity of cytisine (1) and its derivatives [1, 2] makes them a promising class for practical application. On the other hand, the chiral 3,7-diazobicyclo[3.3.1]nonane skeleton is interesting for studying structural features of substituted cytisines [3][4][5][6]. Until now, a large number of cytisine derivatives with various groups on the N atom have been synthesized [7][8][9][10][11][12], including acryloyl groups [13], thiazoles, benzthiazoles [11], and 1,2,4-thiadiazole groups [12]. In continuation of our research on transformations of 1 [11,12] and in order to find biologically active compounds in this series, we synthesized acyl derivatives via acylation of 1 with acetic anhydride and acid chlorides. The acylating agents were acetic anhydride; benzoyl-and o-bromo-and p-nitrobenzoyl chlorides; and crotonyl and cinnamoyl chlorides. The reaction with acetic anhydride occurred with an excess of it. Acylation by the acid chlorides occurred in anhydrous toluene under reflux: R = -ÑH 3 (2); -Ñ 6 H 5 (3); -Ñ 6 H 4 -Br-o (4); -C 6 H 4 -NO 2 -n (5); -CH=CH-C 6 H 5 (6); -CH=CH-CH 3 (7) Acylation of 1 by acid chlorides was carried out without a HCl acceptor. Atom N12 of ring C played this role. Structures of 2-7 were confirmed by IR and PMR spectra and by an x-ray structure analysis (XSA) for N-o-bromobenzoylcytisine (4), N-p-nitrobenzoylcytisine (5), and N-crotonylcytisine (6).IR spectra contained absorption bands at 1643-1653 cm -1 (ν CO ) and 1634-1647 (ν CO ). The physicochemical properties of 2, 3, and 7 agreed with those published. PMR spectra of the N-acylcytisines in solution characteristically showed several rotational isomers around the N12-CO and CO-R bonds. They could produce spectra of several conformers or simply give very broad spectral lines because the barriers to rotation were small. In several instances resonances could not be unambiguously assigned.

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